Design and Combinatorial Development of Shield-1 Peptide Mimetics Binding to Destabilized FKBP12

The destabilizing domain (DD) is a double point-mutated version of the human protein FKBP12, and it has proven its vast utility in several biological systems, where the level of a fused protein-of-interest may be controlled by the addition of the stabilizing small molecule Shield-1 (Shld1). With the aim of developing small peptide derived ligands that mimic the Shld1-DD interaction, we here report the synthesis and screening of a one-bead one-compound library consisting of triazole containing tripeptides. The library of peptide mimetics was synthesized on MicroParticle Matrix encoded PEGA1900 beads and deconvoluted using a decoder apparatus. Verification of the hit’s activities was performed using an on-bead binding assay, where the binding profile of the immobilized substrates were correlated to a solid-supported version of the known SLF* ligand. These studies guided the design of small peptide-like compounds, which were readily synthesized in solution or on solid-support. The binding affinity of these f...